The current inhibitor-based drug paradigm not only limits drug targets to those proteins with a tractable active site, but also requires high dosing in order to achieve adequate IC90 concentrations for therapeutic efficacy. To circumvent these issues, alternative therapeutic strategies have been employed to specifically knock down target proteins. While genetic techniques such as RNAi, and CRISPR/Cas9 can significantly reduce protein levels, the pharmacokinetic properties (i.e., metabolic stability and tissue distribution) associated with these approaches have so far limited their development as clinical agents.
The pathologic fusion protein BCR-ABL is a constitutively active tyrosine kinase that drives uncontrolled cell proliferation, resulting in chronic myelogenous leukemia (CML). With the advent of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL, CML has become a chronic but manageable disease. For example, imatinib mesylate, the first TKI developed against BCR-ABL, binds competitively at the ATP-binding site of c-ABL and inhibits both c-ABL and the oncogenic fusion protein BCR-ABL. Second generation TKIs (such as dasatinib and bosutinib) were subsequently developed to treat CML patients with acquired resistance to imatinib. Despite the remarkable success of BCR-ABL TKIs, all CIVIL patients must remain on treatment for life because the TKIs are not curative due to persistent leukemic stem cells (LSCs).
There is thus an unmet need in the art for novel compositions and methods to knock down c-ABL and/or BCR-ABL in a cell. Such methods could be used to treat and/or prevent CML in a mammal. The present invention addresses this need.